Heretofore, many anticancer agents have been developed and used in the medical field. For example, tegafur is a anticancer agent that is activated in vivo and gradually releases the active form, i.e., 5-fluorouracil (hereinafter referred to as “5-FU”), thereby lessening the toxicity or side effects presented by 5-FU. A combination drug containing the three pharmaceutical agents of tegafur, gimeracil and oteracil potassium (trade name: TS-1, molar ratio of tegafur/gimeracil/oteracil potassium=1:0.4:1, manufactured by Taiho Pharmaceutical Co., Ltd., hereunder this combination drug is referred to as TS-1) has a further stronger antitumor effect because gimeracil inhibits the degradation of 5-FU. In this preparation, since oteracil potassium specifically inhibits the onset of gastrointestinal toxicity that is likely to be accompanied by the potentiation of the antitumor effect attained by the two pharmaceutical agents, i.e., tegafur and gimeracil, the therapeutic effect being thereby improved. TS-1 therefore contributes to the treatment of various malignant tumors (Patent Document 1).
However, therapeutic agents and methods which have stronger therapeutic effects enough to prolong the survival of cancer patients are still deemed necessary. Administering combination chemotherapy of various agents (combination therapy), whose mechanism of action of antitumor effect and/or side effect are differ from one another, is attempted to improve therapeutic effect and some combination therapies actually contribute to improvement of cancer treatment (see, for example, Patent Documents 2, 3 and 4). For example, oxaliplatin exhibits a low antitumor effect when used alone, and is therefore used in combination with other pharmaceutical agents. Combination therapy using 5-fluorouracil and folinate (hereunder, folinate is referred to as LV) (FOLFOX) are commonly used worldwide (see, for example, Non-Patent Documents 1, 2, and 3). However, the application of FOLFOX is complicated and extended periods of infusional 5-FU reduce patient's QOL because of the physical restraint that accompanies continuous intravenous infusion, moreover, high medical costs. Therefore developments of better combination therapies using oxaliplatin are being made all over the world. As an example, a combination therapy using oxaliplatin and capecitabine (trade name: Xeloda), which is an oral fluorinated pyrimidine, (XELOX) is reported to provide an antitumor effect almost identical to FOLFOX (see, for example, Non-Patent Document 4). As a novel approach has been indicated that TS-1 and oxaliplatin provides remarkable antitumor effect, as in this case, that has superior therapeutic efficacy to the case oxaliplatin in combination with capecitabin (Patent Document 5). However, a stronger therapeutic effect is still required.
As described above, oxaliplatin exhibits a low antitumor effect when used singly and one of the reason is a low accumulation of the agents in tumor tissue. When an antitumor agent is administered, it may quickly disappear from the blood circulation or be distributed to healthy organs; therefore, the antitumor agent does not accumulate in the tumor tissue effectively. Accordingly, many antitumor agents cannot always exhibit a sufficient antitumor activity, and they often undesirably affect normal tissues (side effects), causing critical toxicity. Enhancing efficacy of antitumor agents is an important object in current cancer chemotherapies, and development of drug delivery system (DDS) by which drugs can effectively accumulate in tumor is strongly desired.
Liposome is a closed vesicle comprising phospholipids, which are derived from biological material, as a main component. So liposomes exhibits low toxicity and antigenicity when administered to a living body. Furthermore, some reports indicate that encapsulation of drugs in liposome enables to control their stability in blood and biodistribution, resulting in improved delivery efficiency of their payloads to the targeted tissues (Patent Documents 6, 7 and 8 and Non-Patent Document 5). It is also known that vesicles such as liposome which has a particle size of 100 to 200 nm effectively accumulate in tumor, because angiogenic vessels present in tumor show relatively high permeability compared with blood vessels in healthy tissue (Non-Patent Document 6).
Patent Document 1: Japanese Patent No. 2614164
Patent Document 2: Japanese Patent No. 2557303
Patent Document 3: Japanese Unexamined Patent Publication No. 1996-169825
Patent Document 4: Japanese Unexamined Patent Publication No. 2002-205945
Patent Document 5: WO2005/120480
Patent Document 6: WO95/24201
Patent Document 7: Japanese Patent No. 3415131
Patent Document 8: Japanese Unexamined Patent Publication No. 2006-248978
Non-Patent Document 1: Journal of Clinical Oncology, Vol. 22, 23-30, 2004
Non-Patent Document 2: Journal of Clinical Oncology, Vol. 21, 2059-2069, 2003
Non-Patent Document 3: Journal of Clinical Oncology, Vol. 18, 2938-2947, 2000
Non-Patent Document 4: Journal of Clinical Oncology, Vol. 22, 2084-2091, 2004
Non-Patent Document 5: Journal of Liposome Research, Vol. 4, 667-687, 1994
Non-Patent Document 6: Drug Delivery System, Vol. 14, 433-447, 1999